Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15
Open accessAbstract
Background & aims Host genetic factors are likely to contribute to the variable course of hepatic fibrosis in response to chronic liver injury. Similarly, the fibrotic response differs among inbred mouse strains after challenge with CCl(4). Our aim was to identify unknown susceptibility loci for hepatic fibrosis in a cross between fibrosis-susceptible and -resistant inbred mice. Methods Seven inbred mouse strains were treated with CCl(4), and hepatic fibrosis was phenotypically characterized by histology, hepatic hydroxyproline levels, and serum surrogate markers. F(1) hybrids of susceptible BALB/cJ and resistant A/J inbred strains were intercrossed to obtain 358 F(2) progeny. Quantitative trait loci (QTL) that determine hepatic fibrosis were identified by genome-wide interval mapping and haplotype analysis. Results In this model, marked strain differences in fibrosis susceptibility exist, with BALB/c inbred mice being most susceptible. The hydroxyproline levels of F(1) mice resemble the resistant parental strains, indicating that fibrosis susceptibility is a recessive trait. QTL analysis identifies a susceptibility locus on chromosome 15 that significantly affects the stage of fibrosis and hydroxyproline levels. According to standard nomenclature, this locus is called Hfib1 (hepatic fibrogenic gene 1). Hfib1 is defined by genetic markers D15Mit26 and D15Mit122. A suggestive QTL on chromosome 2 colocalizes with the complement factor 5 gene, known to be mutated in the resistant strain A. Conclusions The set of inbred strains provides a framework for systematic analysis of fibrogenic genes. QTL mapping is useful to identify genetic susceptibility loci for hepatic fibrosis that might harbor new molecular targets for antifibrotic drug design.
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In inbred mouse strains, different genetic makeup determines susceptibility to liver fibrosis, ranging from fibrosis resistance in A/J mice to high susceptibility in BALB/c.
“A similar phenomenon, the precise mechanism of which is poorly understood, has been reported in inbred mouse strains, where different genetic makeup determines susceptibility to liver fibrosis. This ranges from fibrosis resistance in A/J mice to high susceptibility in the BALB/c strain2,3.”
From Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis (2020) · cites this paper as [2]
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Safadi, R., Ohta, M., Alvarez, C. E., Fiel, M. I., Bansal, M. B., Mehal, W. Z., & Friedman, S. L. (2004)
- Authors
- Hillebrandt, S., Goos, C., Matern, S., & Lammert, F.
- Affiliations
- Universitätsklinikum Aachen (DE)
- ORCID
- Lammert, Frank
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 123
- Issue
- 6
- Pages
- 2041-2051
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2041712989
- Cited by
- 104
- References
- 62
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 8 · 2019: 6 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 6 · 2013: 6 · 2012: 8
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- liver fibrosis, genetic susceptibility, chromosome 15, quantitative trait loci, inbred mouse strains, carbon tetrachloride, hydroxyproline
- MeSH terms
- Animals, Chromosome Mapping, Haplotypes, Hybridization, Genetic, Liver Cirrhosis, Mice, Inbred Strains, Phenotype, Genome, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Mice
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